Organic compounds

ABSTRACT

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT 2A  receptor, serotonin transporter (SERT) and/or pathways involving dopamine D 2  receptor signaling systems.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Nos. 61/624,293, 61/624,292 and 61/624,291, all filed on Apr. 14, 2012; and U.S. Provisional Application Nos. 61/671,723 and 61/671,713, both filed on Jul. 14, 2012, the contents of each of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to particular substituted heterocycle fused gamma-carbolines, in free, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT_(2A) receptor, serotonin transporter (SERT) and/or pathways involving dopamine D₂ receptor signaling systems, e.g., diseases or disorders such as anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility and obesity; depression and mood disorders associated with psychosis or Parkinson's disease; psychosis such as schizophrenia associated with depression; bipolar disorder; and other psychiatric and neurological conditions, as well as to combinations with other agents.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonists or antagonists of 5-HT2 receptors, particularly 5-HT_(2A) and 5-HT_(2C) receptors, in treating central nervous system disorders. These compounds have been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compounds useful for the treatment of disorders associated with 5-HT_(2A) receptor modulation such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility, and obesity.

PCT/US08/03340 (WO 2008/112280) and U.S. application Ser. No. 10/786,935 disclose methods of making substituted heterocycle fused gamma-carbolines and uses of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders.

WO/2009/145900 discloses use of particular substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and/or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders associated with psychosis and/or depression, this patent application discloses and claims use of these compounds at a low dose to selectively antagonize 5-HT_(2A) receptors without affecting or minimally affecting dopamine D₂ receptors, thereby useful for the treatment of sleep disorders without the side effects of the dopamine D₂ pathways or side effects of other pathways (e.g., GABA_(A)receptors) associated with convention sedative-hypnotic agents (e.g., benzodiazepines) including but not limited to the development of drug dependency, muscle hypotonia, weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pains, and chest pains.

WO 2009/114181 discloses methods of preparing toluenesulfonic acid addition salt crystals of particular substituted heterocycle fused gamma-carbolines, e.g., toluenesulfonic acid addition salt of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

WO 2011/133224 discloses prodrugs/metabolites of substituted heterocycle fused gamma-carboline for improved formulation, e.g., extended/controlled release formulation. This application discloses that heterocycle fused gamma-carboline N-substituted with a 4-fluorophenyl(4-hydroxy)butanyl moiety are shown to have high selectivity for the serotonin transporter (SERT) relative to the heterocycle fused gamma-carboline containing 4-fluorophenylbutanone. The hydroxy group on these compounds, however, is inter-converted to and from the ketone within the plasma and the brain, allowing it to serve as a reservoir for the 4-fluorophenylbutanone drug.

For the first time, the current invention provides compounds which block the in vivo inter-conversion between the hydroxy and the ketone, yielding compounds which antagonize 5-HT2A receptors and also inhibit serotonin re-uptake transporter.

SUMMARY OF THE INVENTION

In the first aspect, the invention provides a compound of formula I:

wherein:

X is N(H), N(C₁₋₄alkyl) or O;

R¹ is H or C₁₋₆alkyl (e.g., methyl);

R² is H or OR³ wherein R³ is H or C₁₋₆alkyl (e.g., methyl);

provided that R¹ and R² are not both H, and R¹ and R³ are not both H; in free or salt form.

In a further embodiment, the invention provides the Compound of Formula I, in free or salt form as described in the following formulae:

-   -   1.1 the compound of Formula I, wherein R² is OR³;     -   1.2 the compound of Formula I or 1.1, wherein R¹ is C₁₋₆alkyl         (e.g., methyl);     -   1.3 the compound of Formula I, 1.1 or 1.2, wherein R¹ is methyl;     -   1.4 the compound of Formula I or any of formulae 1.1-1.3,         wherein R² is OR³ and R³ is C₁₋₆alkyl (e.g., methyl);     -   1.5 the compound of Formula I or any of formulae 1.1-1.4,         wherein R² is OR³ and R³ is methyl;     -   1.6 the compound of Formula I or any of formulae 1.1-1.5,         wherein X is N(H), N(C₁₋₄alkyl) or O;     -   1.7 the compound of Formula I or any of formulae 1.1-1.6,         wherein X is O;     -   1.8 the compound of Formula I or any of formulae 1.1-1.6,         wherein X is N(H);     -   1.9 the compound of Formula I or any of formulae 1.1-1.6,         wherein X is N(C₁₋₄alkyl;     -   1.10 the compound of Formula I or any of formulae 1.1-1.6,         wherein X is N(CH₃);     -   1.11 the Compound of Formula I or any of formulae 1.1-1.10,         wherein the Compound is:

-   -   1.12 the Compound of Formula I or any of 1.1-1.11, wherein the         Compound is:

-   -   1.13 the Compound of Formula I or any of 1.11-1.12, wherein the         Compound is in substantially pure diastereomeric form (i.e.,         substantially free from other diastereomers);     -   1.14 the Compound of Formula I or any of 1.1-1.13, wherein the         Compound has a diasteromeric excess of greater than 70%,         preferably greater than 80%, more preferably greater than 90%         and most preferably greater than 95%; in free or salt form.

In a further embodiment of the first aspect, the invention provides a compound of Formula I, in free or salt form as described in the following formulae:

-   -   4.1 the Compound of Formula I or any of 1.1-1.14, wherein the         salt is selected from a group consisting of hydrochloric,         hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic,         propionic, succinic, glycolic, stearic, lactic, malic, tartaric,         citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,         glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,         fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,         oxalic, isethionic, and the like;     -   4.2 the Compound of Formula I or formula 4.1, wherein the salt         is fumaric acid addition salt;     -   4.3 the Compound of Formula I or formula 4.1, wherein the salt         is phosphoric acid addition salt;     -   4.4 the Compound of Formula I or formula 4.1, wherein the salt         is a toluenesulfonic acid addition salt;

In the second aspect, the invention provides a pharmaceutical composition comprising the compound of formula I, or any of 1.1-1.14 or 4.1-4.4 (the Compounds of the Invention), in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

In a further embodiment of the second aspect, the Pharmaceutical Composition of the Invention is for a sustained or delayed release, e.g., depot, formulation. In one embodiment, the depot formulation comprises the Compounds of the Invention in a polymeric matrix. In another embodiment, the Compounds of the Invention are dispersed or dissolved within the polymeric matrix. In a further embodiment, the polymeric matrix comprises standard polymers used in depot formulations such as polymers selected from a polyester of a hydroxyfatty acid and derivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate, a polyalkylene oxalate, a polyortho ester, a polycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, and mixtures thereof. In a further embodiment, the polymer is selected from a group consisting of polylactide, poly d,l-lactide, poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. In a particular embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide). Any of the Compositions hereinbefore described may be a pharmaceutical composition wherein said composition is in admixture with a pharmaceutically acceptable diluent or carrier.

The (Pharmaceutical) depot formulations as hereinbefore described are particularly useful for sustained or delayed release, wherein the Compounds of the Invention are released upon degradation of the polymeric matrix. These Compositions may be formulated for controlled- and/or sustained-release of the Compounds of the Invention (e.g., as a depot composition) over a period of up to 180 days, e.g., from about 14 to about 30 to about 180 days. For example, the polymeric matrix may degrade and release the Compounds of the Invention over a period of about 30, about 60 or about 90 days. In another example, the polymeric matrix may degrade and release the Compounds of the Invention over a period of about 120, or about 180 days.

In still another further embodiment, the Pharmaceutical Compositions of the Invention, particularly the depot compositions of the Invention are formulated for administration by injection.

In the third aspect, the invention provides the Compounds of the Invention as hereinbefore described in an osmotic controlled release oral delivery system (OROS), which is described in WO 2000/35419 and EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents of each of which applications are incorporated by reference in their entirety. Therefore in one embodiment of the third aspect, the invention provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing a Compound of the Invention in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention, as hereinbefore described; (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) and orifice formed or formable through the wall. (Composition P.1)

In another embodiment of the third aspect, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compounds of the Invention in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention as hereinbefore described, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semi-permeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall. (Composition P.2)

In still another embodiment of the third aspect, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of the Invention in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention as hereinbefore described, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expandable layer and the environment at the exit orifice. (Composition P.3)

In still another embodiment of the third aspect, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of the Invention in free or pharmaceutically acceptable salt form or a Pharmaceutical Composition of the Invention as hereinbefore described, the gelatin capsule being surrounded by a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semi-permeable layer encompassing at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use. (Composition P.4). The expandable layer may be formed in one or more discrete sections, such as for example, two sections located on opposing sides or ends of the gelatin capsule.

In a particular embodiment of the third aspect, the Compound of the Inventions in the Osmotic-controlled Release Oral delivery System (i.e., in Composition P.1-P.4) are in a liquid formulation, which formulation may be neat, liquid active agent, liquid active agent in a solution, suspension, emulsion or self-emulsifying composition or the like.

Further information on Osmotic-controlled Release Oral delivery System composition including characteristics of the gelatin capsule, barrier layer, an expandable layer, a semi-permeable layer; and orifice may be found in WO 2000/35419, the contents of which are incorporated by reference in their entirety. Other Osmotic-controlled Release Oral delivery System for the Compound or the Pharmaceutical Composition of the Invention may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contents of which are incorporated by reference in their entirety.

Therefore, in another embodiment of the third aspect, the invention provides a composition or device comprising (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprises the Compound of the Invention, in free or pharmaceutically acceptable salt form, or a Pharmaceutical Composition as herein before described said second layer comprises a polymer; (b) an outer wall surrounding said two or more layers; and (c) an orifice in said outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membrane surrounding a three-layer-core: in these embodiments the first layer is referred to as a first drug layer and contains low amounts of drug (e.g., the Compounds of the Invention) and an osmotic agent such as salt, the middle layer referred to as the second drug layer contains higher amounts of drug, excipients and no salt; and the third layer referred to as the push layer contains osmotic agents and no drug. At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment, the membrane surrounding an inner protective subcoat, at least one exit orifice formed or formable therein and at least a portion of the membrane being semi-permeable; an expandable layer located within the compartment remote from the exit orifice and in fluid communication with the semi-permeable portion of the membrane; a first drug layer located adjacent the exit orifice; and a second drug layer located within the compartment between the first drug layer and the expandable layer, the drug layers comprising the Compound of the Invention in free or pharmaceutically acceptable salt thereof. Depending upon the relative viscosity of the first drug layer and second drug layer, different release profiles are obtained. It is imperative to identify the optimum viscosity for each layer. In the present invention, viscosity is modulated by addition of salt, sodium chloride. The delivery profile from the core is dependent on the weight, formulation and thickness of each of the drug layers. (Composition P.7)

In a particular embodiment, the invention provides Composition P.7 wherein the first drug layer comprising salt and the second drug layer containing no salt. Composition P.5-P.7 may optionally comprise a flow-promoting layer between the membrane and the drug layers. Compositions P.1-P.7 will generally be referred to as Osmotic-controlled Release Oral delivery System Composition.

In the fourth aspect, the invention provides a method (Method I) for the treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof, a Compound of Formula I or any of formulae 1.1-1.14, in free or pharmaceutically acceptable salt form as described in any of 4.1-4.4, or a pharmaceutical composition as hereinbefore described.

In a further embodiment of the fourth aspect, the invention provides Method I wherein the method is further as described in the following formulae:

-   -   7.1 Method I, wherein the central nervous system disorder is one         or more disorders associated with dementia, e.g., disorders         associated with mild cognition impairment and dementing         illnesses including senile dementia, Alzheimer's disease, Pick's         disease, frontotemporal dementia, parasupranculear palsy,         dementia with Lewy bodies, vascular dementia, Huntington's         disease, Parkinson's disease, multiple sclerosis, amyotrophic         lateral sclerosis, Down syndrome, elderly depression,         Wernicke-Korsakoffs syndrome, corticobasal degenerations and         prion disease;     -   7.2 Method I or 7.1, wherein the disorders associated with         dementia is selected from the group consisting of (1) behavioral         or mood disorders such as agitation/irritation,         aggressive/assaultive behavior, anger, physical or emotional         outbursts; (2) psychosis; (3) depression; and (4) sleep         disorders;     -   7.3 Method I or 7.1, wherein the central nervous system disorder         is agitation/irritation, aggressive/assaultive behavior, anger,         physical or emotional outbursts;     -   7.4 Method I, wherein the central nervous system disorder is a         disorder selected from a group consisting of obesity, anxiety,         depression (for example refractory depression and MDD),         psychosis, schizophrenia, sleep disorders (particularly sleep         disorders associated with schizophrenia and other psychiatric         and neurological diseases), sexual disorders, migraine,         conditions associated with cephalic pain, social phobias,         agitation in dementia (e.g., agitation in Alzheimer's disease),         agitation in autism and related autistic disorders, and         gastrointestinal disorders such as dysfunction of the         gastrointestinal tract motility;     -   7.5 Method I or any of 7.1-7.4, wherein the central nervous         system disorder is a disorder involving serotonin 5-HT_(2A),         dopamine D2 receptor system and/or serotonin reuptake         transporter (SERT) pathways as similarly described in         WO/2009/145900, the contents of which are herein incorporated by         reference in their entirety;     -   7.6 Method I or any of Formulae 7.1-7.5, wherein the central         nervous system disorder is a disorder involving serotonin         reuptake transporter (SERT) pathways;     -   7.7 Method I or any of Formulae 7.1-7.6, wherein the central         nervous system disorder is a disorder selected from the         following: (i) psychosis, e.g., schizophrenia, in a patient         suffering from depression; (2) depression in a patient suffering         from psychosis, e.g., schizophrenia; (3) mood disorders         associated with psychosis, e.g., schizophrenia or Parkinson's         disease; and (4) sleep disorders associated with psychosis,         e.g., schizophrenia or Parkinson's disease; (5) depression; (6)         anxiety; (7) post-traumatic stress disorder; or (8) impulse         control disorder, e.g., intermittent explosive disorder;     -   7.8 Method I or any of Formulae 7.1-7.7, wherein the central         nervous system disorder is psychosis, e.g., schizophrenia and         said patient is a patient suffering from depression;     -   7.9 Method I or any of Formulae 7.1-7.8, wherein said patient is         unable to tolerate the side effects of convention antipsychotic         drugs, e.g., chlorpromazine, haloperidol droperidol,         fluphenazine, loxapine, mesoridazine molidone, perphenazine,         pimozide, prochlorperazine promazine, thioridazine, thiothixene,         trifluoperazine, clozapine, aripiparazole, olanzapine,         quetiapine, risperidone and ziprasidone;     -   7.10 Method I or any of Formulae 7.1-7.9, wherein said patient         is unable to tolerate the side effects of convention         antipsychotic drugs, e.g., haloperidol, aripiparazole,         clozapine, olanzapine, quetiapine, risperidone, and zipasidone;     -   7.11 Method I or any of Formulae 7.1-7.10, wherein said disorder         is depression and said patient is a patient suffering from         psychosis, e.g., schizophrenia, or Parkinson's disease;     -   7.12 Method I or any of Formulae 7.1-7.6, wherein said disorder         is sleep disorder and said patient is suffering from depression;     -   7.13 Method I or any of 7.1-7.6, wherein said one or more         disorders is sleep disorder and said patient is suffering from         psychosis, e.g., schizophrenia;     -   7.14 Method I or any of 7.1-7.6, wherein said one or more         disorders is sleep disorder and said patient is suffering from         Parkinson's disease;     -   7.15 Method I or any of 7.1-7.6, wherein said one or more         disorders is sleep disorder and said patient is suffering from         depression and psychosis, e.g., schizophrenia, or Parkinson's         disease.     -   7.16 Any of the foregoing methods, wherein the effective amount         is 1 mg-1000 mg, preferably 2.5 mg-50 mg, still preferably 1-40         mg, e.g., 1-10 mg, e.g., 10 mg, 20 mg, greater 20 mg, e.g., 30         mg, 40 mg;     -   7.17 Any of the foregoing methods, wherein the effective amount         is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day, still         preferably 1-40 mg/day, e.g., 1-10 mg/day, e.g., 10 mg/day, 20         mg/day, greater 20 mg/day, e.g., 30 mg/day, 40 mg/day;     -   7.18 Any of the foregoing methods wherein a condition to be         treated is dyskinesia, e.g. in a patient receiving dopaminergic         medications, e.g., medications selected from levodopa and         levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B         inhibitors), dopamine agonists, and anticholinergics, e.g.,         levodopa;     -   7.19 Any of the foregoing methods wherein the patient suffers         from Parkinson's disease.     -   7.20 Any of the foregoing methods wherein the patient does not         respond to a selective serotonin re-uptake inhibitor, e.g.         selected from one or more of citalopram (Celexa, Cipramil,         Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,         Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,         Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,         Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox         (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine         (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine         (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,         Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,         Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);         vilazodone (Viibryd); or zimelidine (Zelmid, Normud).     -   7.21 Any of the foregoing methods wherein the patients is also         receiving a selective serotonin re-uptake inhibitor, e.g.         selected from one or more of citalopram (Celexa, Cipramil,         Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox,         Cital); dapoxetine (Priligy); escitalopram (Lexapro, Cipralex,         Seroplex, Esertia); fluoxetine (Depex, Prozac, Fontex, Seromex,         Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox         (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)); fluvoxamine         (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox); indalpine         (Upstene); paroxetine (Paxil, Seroxat, Sereupin, Aropax,         Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine,         Deparoc); sertraline (Zoloft, Lustral, Serlain, Asentra);         vilazodone (Viibryd); or zimelidine (Zelmid, Normud).     -   7.22 Any of the foregoing methods wherein the patients is         suffering from autistic spectrum disorder, e.g., autism or         Asperger Syndrome.     -   7.23 Any of the foregoing methods wherein the patients is         suffering from dementia, e.g., disorders associated with mild         cognition impairment and dementing illnesses including senile         dementia, Alzheimer's disease, Pick's disease, frontotemporal         dementia, parasupranculear palsy, dementia with Lewy bodies,         vascular dementia, Huntington's disease, Parkinson's disease,         multiple sclerosis, amyotrophic lateral sclerosis, Down         syndrome, elderly depression, Wernicke-Korsakoff's syndrome,         corticobasal degenerations and prion disease.     -   7.24 Any of the foregoing methods wherein the patient is also         receiving a cholinesterase inhibitor (e.g., acetylcholinesterase         inhibitor) or an N-Methyl D-Asparate (NMDA) receptor antagonist,         in free or pharmaceutically acceptable salt form.     -   7.25 Method 7.24, wherein the cholinesterase inhibitor (e.g.,         acetylcholinesterase inhibitor) is selected from the group         consisting of Tacrine, rivastigmine (Exelon), donepezil         (Aricept), and galantamine (Razadyne, formerly called Reminyl))         in free or pharmaceutically acceptable salt form.     -   7.26 Method 7.24, wherein the cholinesterase inhibitor (e.g.,         acetylcholinesterase inhibitor) is donepezil in free or         pharmaceutically acceptable salt form.     -   7.27 Method 7.24, wherein the NMDA receptor antagonist is         memantine in free or pharmaceutically acceptable salt form.

In a particular embodiment of the fourth aspect, the invention provides a method (Method I_(P)) for the treatment or prophylaxis of a central nervous system disorder as hereinbefore described, comprising administering to a patient in need thereof:

-   -   7.4P a compound of Formula I or any of formulae 1.1-1.14, in         free or (pharmaceutically acceptable) salt form as described in         any of 4.1-4.4;     -   7.8P a Pharmaceutical or Depot Composition as hereinbefore         described; or     -   7.11P Osmotic-controlled Release Oral delivery System         Composition as hereinbefore described.

In a further embodiment of the fourth aspect, the invention provides Method I_(P), wherein the method is further described in any one of formulae 7.1-7.27.

In a particular embodiment of the fourth aspect, the invention provides Method I or any of 7.1-7.27, wherein the disorder is schizophrenia or sleep disorder.

In a particular embodiment of the fourth aspect, the invention provides Method I or any of 7.1-7.27, wherein the disorder is depression or anxiety.

In a particular embodiment of the fourth aspect, the invention provides Method I or any of 7.1-7.27, wherein the disorder is post-traumatic stress disorder or an impulse control disorder, e.g., intermittent explosive disorder.

In a particular embodiment of the fourth aspect, the invention provides Method I or any of 7.1-7.27, wherein the disorder is post-traumatic stress disorder or an impulse control disorder, e.g., intermittent explosive disorder in a patient suffering from dementia, e.g., senile dementia, Alzheimer's disease, Pick's disease, frontotemporal dementia, parasupranculear palsy, dementia with Lewy bodies, vascular dementia, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoffs syndrome, corticobasal degenerations and/or prion disease.

In still another embodiment of the fourth aspect, the invention provides Method I or any of 7.1-7.27, wherein the Depot Composition of the Invention is administered for controlled- and/or sustained-release of the Compounds of the Invention over a period of from about 14 days, about 30 to about 180 days, preferably over the period of about 30, about 60 or about 90 days. Controlled- and/or sustained-release is particularly useful for circumventing premature discontinuation of therapy, particularly for antipsychotic drug therapy where non-compliance or non-adherence to medication regimes is a common occurrence.

In the fifth aspect, the invention provides a method (Method II) for the prophylaxis or treatment one or more sleep disorders, agitation, aggressive behaviors, post-traumatic stress disorder and/or impulse control disorder, e.g., intermittent explosive disorder, comprising administering to a patient in need thereof a compound as described in the following formulae:

-   -   8.1 a compound of Formula I or any of formulae 1.1-1.14, in free         or (pharmaceutically acceptable) salt form as described in any         of 4.1-4.4;     -   8.2 a Pharmaceutical or Depot Composition as hereinbefore         described;     -   8.3 Osmotic-controlled Release Oral delivery System Composition         as hereinbefore described.

In one embodiment of the fifth aspect, the invention provides Method II or any of 8.1-8.3, wherein the disorder is sleep disorders. In another embodiment of the fifth aspect, the invention provides Method II, wherein the disorder is agitation, aggressive behaviors, post-traumatic stress disorder and/or impulse control disorder, e.g., intermittent explosive disorder.

In a further embodiment of the fifth aspect, the invention provides Method II, 8.1-8.3, wherein the sleep disorder includes sleep maintenance insomnia, frequent awakenings, and waking up feeling unrefreshed;

-   -   8.11 Any of the foregoing methods, wherein the sleep disorder is         sleep maintenance insomnia;     -   8.12 Any of the foregoing methods, wherein the effective amount         is 1 mg-10 mg per day, e.g., 1 mg-5 mg, preferably 2.5-5 mg, per         day, still preferably 10 mg per day;     -   8.13 Any of the foregoing methods, wherein the effective amount         is 2.5 mg or 5 mg, per day or 10 mg per day;     -   8.14 Any of the foregoing methods wherein the sleep disorder is         in a patient suffering from or at risk of dyskinesia, e.g., a         patient receiving dopaminergic medications, e.g., selected from         levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,         MAO-B inhibitors), dopamine agonists, and anticholinergics,         e.g., receiving levodopa;     -   8.15 Any of the foregoing methods wherein the patient suffers         from Parkinson's disease.

The Compounds of Invention provide effective treatment of 5-HT_(2A), SERT and/or D₂ receptor related disorders without or with minimal extrapyramidal side effects as similarly disclosed and claimed in WO 2009/145900, the contents of which are incorporated by reference in their entirety. Therefore, the Compounds of the Invention, the Pharmaceutical Compositions of the Invention or the Depot Compositions of the Invention may be used in combination with a second therapeutic agent, particularly at lower dosages than when the individual agents are used as a monotherapy so as to enhance the therapeutic activities of the combined agents without causing the undesirable side effects commonly occur in conventional monotherapy. Therefore, the Compounds of the Invention may be simultaneously, sequentially, or contemporaneously administered with other anti-depressant, anti-psychotic, other hypnotic agents, and/or agents use to treat Parkinson's disease or mood disorders or dementia. In another example, side effects may be reduced or minimized by administering a Compound of the Invention in combination with one or more second therapeutic agents in free or salt form, wherein the dosages of (i) the second therapeutic agent(s) or (ii) both Compound of the Invention and the second therapeutic agent, are lower than if the agent/compound are administered as a monotherapy. In a particular embodiment, the Compounds of the Invention are useful to treat dyskinesia in a patient receiving dopaminergic medications, e.g., selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., such as are used in the treatment of Parkinson's disease.

Therefore, in the sixth aspect, the current invention provides Method I, e.g., or any of formulae 7.1-7.27, or Method II or any of 8.1-8.15, further comprises one or more therapeutic agents selected from compounds that modulate GABA activity (e.g., enhances the activity and facilitates GABA transmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist, etc.), a melatonin agonist, an ion channel modulator (e.g., blocker), a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist or antagonist, a noradrenergic agonist or antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, an anti-depressant, and an antipsychotic agent, e.g., an atypical antipsychotic agent, in free or pharmaceutically acceptable salt form (Method I-A and II-A respectively).

In another embodiment of the sixth aspect, Method I-A and II-A, Method I, e.g., or any of formulae 7.1-7.27, or Method II or any of 8.1-8.15, further comprises one or more therapeutic agents selected from a cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) or an N-Methyl D-Asparate (NMDA) receptor antagonist, in free or pharmaceutically acceptable salt form. In a specific embodiment, the cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) is selected from the group consisting of Tacrine, rivastigmine (Exelon), donepezil (Aricept), and galantamine (Razadyne, formerly called Reminyl)) in free or pharmaceutically acceptable salt form. In a further embodiment, the cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in free or pharmaceutically acceptable salt form. In another embodiment, the NMDA receptor antagonist is memantine in free or pharmaceutically acceptable salt form.

In a further embodiment of the sixth aspect, the invention provides Method I-A or II-A as follows, further comprising one or more therapeutic agents.

-   -   9.1 Method I-A or II-A, wherein the therapeutic agent(s) is         compounds that modulate GABA activity (e.g., enhances the         activity and facilitates GABA transmission);     -   9.2 Method I-A or II-A or 9.1, wherein the GABA compound is         selected from a group consisting of one or more of doxepin,         alprazolam, bromazepam, clobazam, clonazepam, clorazepate,         diazepam, flunitrazepam, fiurazepam, lorazepam, midazolam,         nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,         eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,         tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;     -   9.3 Method I-A or II-A, wherein the therapeutic agent is an         additional 5HT_(2A) antagonist;     -   9.4 Method I-A or II-A or 9.3, wherein said additional 5HT_(2A)         antagonist is selected from one or more of ketanserin,         risperidone, eplivanserin, volinanserin (Sanofi-Aventis,         France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY         10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego,         Calif.), and AVE8488 (Sanofi-Aventis, France); Method I-A or         II-A, 9.3 or 9.4 additionally selected from pimavanserin         (ACP-103) and pizotifen;     -   9.5 Method I-A or II-A, wherein the therapeutic agent is a         melatonin agonist;     -   9.6 Method I-A or II-A or 9.5, wherein the melatonin agonist is         selected from a group consisting of one or more of melatonin,         ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162         (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II         Discovery) and agomelatine;     -   9.7 Method I-A or II-A, wherein the therapeutic agent is an ion         channel blocker;     -   9.8 Method I-A or II-A or 9.7, wherein said ion channel blocker         is one or more of lamotrigine, gabapentin and pregabalin.     -   9.9 Method I-A or II-A, wherein the therapeutic agent is an         orexin receptor antagonist;     -   9.10 Method I-A or II-A or 9.9, wherein the orexin receptor         antagonist is selected from a group consisting of orexin, a         1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868         (GlaxoSmithKline) and a benzamide derivative;     -   9.11 Method I-A or II-A, wherein the therapeutic agent is the         serotonin-2 antagonist/reuptake inhibitor (SARI);     -   9.12 Method I-A or II-A or 9.11, wherein the serotonin-2         antagonist/reuptake inhibitor (SARI) is selected from a group         consisting of one or more Org 50081 (Organon-Netherlands),         ritanserin, nefazodone, serzone and trazodone;     -   9.13 Method I-A or II-A, wherein the therapeutic agent is the         5HT1a agonist;     -   9.14 Method I-A or II-A or 9.13, wherein the 5HTIa agonist is         selected from a group consisting of one or more of repinotan,         sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San         Diego, Calif.);     -   9.15 Method I-A or II-A, wherein the therapeutic agent is the         neurokinin-1 drug;     -   9.16 Method I-A or II-A or 9.15, wherein the neurokinin-1 drug         is Casopitant (GlaxoSmithKline);     -   9.17 Method I-A or II-A, wherein the therapeutic agent is an         antipsychotic agent;     -   9.18 Method I-A or II-A or 9.17, wherein the antipsychotic agent         is selected from a group consisting of chlorpromazine,         haloperidol, droperidol, fluphenazine, loxapine, mesoridazine         molidone, perphenazine, pimozide, prochlorperazine promazine,         thioridazine, thiothixene, trifluoperazine, clozapine,         aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone         and paliperidone;     -   9.19 Method I-A or II-A, wherein the therapeutic agent is an         anti-depressant;     -   9.20 Method I-A or II-A or 9.19, wherein the anti-depressant is         selected from amitriptyline, amoxapine, bupropion, citalopram,         clomipramine, desipramine, doxepin, duloxetine, escitaloprame,         fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,         mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine         sulfate, protiptyline, sertraline, tranylcypromine, trazodone,         trimipramine, and velafaxine;     -   9.21 Method I-A or II-A, 9.17 or 9.18, wherein the antipsychotic         agent is an atypical antipsychotic agent;     -   9.22 Method I-A or II-A, or any of 9.17-9.21, wherein the         atypical antipsychotic agent is selected from a group consisting         of clozapine, aripiparazole, olanzapine, quetiapine,         risperidone, ziprasidone, and paliperidone;     -   9.23 Method I-A or II-A, wherein the therapeutic agent is         selected from any of methods 9.1-9.22, e.g., selected from a         group consisting of modafinil, armodafinil, doxepin, alprazolam,         bromazepam, clobazam, clonazepam, clorazepate, diazepam,         flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,         oxazepam, temazapam, triazolam, indiplon, zopiclone,         eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,         tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,         ketanserin, risperidone, eplivanserin, volinanserin         (Sanofi-Aventis, France), pruvanserin, MDL 100907         (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena         Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,         France), repinotan, sarizotan, eptapirone, buspirone, MN-305         (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,         Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,         Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,         lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,         SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a         benzamide derivative, Org 50081 (Organon-Netherlands),         ritanserin, nefazodone, serzone, trazodone, Casopitant         (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,         citalopram, clomipramine, desipramine, doxepin, duloxetine,         escitaloprame, fluoxetine, fluvoxamine, imipramine,         isocarboxazid, maprotiline, mirtazapine, nefazodone,         nortriptyline, paroxetine, phenlzine sulfate, protiptyline,         sertraline, tranylcypromine, trazodone, trimipramine,         velafaxine, chlorpromazine, haloperidol, droperidol,         fluphenazine, loxapine, mesoridazine molidone, perphenazine,         pimozide, prochlorperazine promazine, thioridazine, thiothixene,         trifluoperazine, clozapine, aripiparazole, olanzapine,         quetiapine, risperidone, ziprasidone and paliperidone; In         addition to the therapeutic agents listed herewith, Method I-A         or II-A, is further selected from pimavanserin (ACP-103) and         pizotifen;     -   9.24 Method I-A or II-A wherein the therapeutic agent is an H3         agonist;     -   9.25 Method I-A or II-A, wherein the therapeutic agent is an H3         antagonist;     -   9.26 Method I-A or II-A, wherein the therapeutic agent is a         noradrenergic agonist or antagonist;     -   9.27 Method I-A or II-A, wherein the therapeutic agent is a         galanin agonist;     -   9.28 Method I-A or II-A, wherein the therapeutic agent is a CRH         antagonist;     -   9.29 Method I-A or II-A, wherein the therapeutic agent is a         human growth hormone;     -   9.30 Method I-A or II-A, wherein the therapeutic agent is a         growth hormone agonist;     -   9.31 Method I-A or II-A, wherein the therapeutic agent is         estrogen;     -   9.32 Method I-A or II-A, wherein the therapeutic agent is an         estrogen agonist;     -   9.33 Method I-A or II-A, wherein the therapeutic agent is a         neurokinin-1 drug;     -   9.34 Method I-A or II-A, wherein a therapeutic agent is combined         with compounds of Formula (I) and the therapeutic agent is an         anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,         stalova, Symmetrel, benzotropine, biperiden, bromocryiptine,         entacapone, pergolide, pramipexole, procyclidine, ropinirole,         selegiline and tolcapone;     -   9.35 Method I-A or II-A, wherein compounds of Formula (I) may be         used to treat sleep disorders, depression, pyschosis, or any         combinations thereof, in patients suffering from the listed         diseases and/or Parkinson's disease;     -   9.36 Method I-A or II-A, wherein the disorder is selected from         at least one or more of psychosis, e.g., schizophrenia,         depression, mood disorders, sleep disorders (e.g., sleep         maintenance and/or sleep onset) or any combination of disorders         thereof;     -   9.37 Any of the foregoing methods wherein the disorder is sleep         disorder;     -   9.38 Any of the foregoing methods, wherein the disorder is sleep         disorder associated with psychosis, e.g., schizophrenia or         Parkinson's disease; in free or pharmaceutically acceptable salt         form.

In another embodiment of the sixth aspect, the current invention provides Method I_(P) or Method II_(P) as hereinbefore described, further comprises one or more therapeutic agents selected from compounds that modulate GABA activity (e.g., enhances the activity and facilitates GABA transmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT_(1A)agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist, etc.), a melatonin agonist, an ion channel modulator (e.g., blocker), a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist or antagonist, a noradrenergic agonist or antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, an anti-depressant, and an antipsychotic agent, e.g., an atypical antipsychotic agent, in free or pharmaceutically acceptable salt form (Method I_(P)-A and II_(P)-A respectively). In a further embodiment of this aspect, the invention provides Method I_(P)-A or II_(P)-A as similarly described in any one of formulae 9.1-9.38.

In still another embodiment of the sixth aspect, Method I_(P) or Method II_(P) as hereinbefore described further comprises one or more therapeutic agents selected from a cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) or an N-Methyl D-Asparate (NMDA) receptor antagonist, in free or pharmaceutically acceptable salt form. In a specific embodiment, the cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) is selected from the group consisting of Tacrine, rivastigmine (Exelon), donepezil (Aricept), and galantamine (Razadyne, formerly called Reminyl)) in free or pharmaceutically acceptable salt form. In a further embodiment, the cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in free or pharmaceutically acceptable salt form. In another embodiment, the NMDA receptor antagonist is memantine in free or pharmaceutically acceptable salt form.

In the seventh aspect of the invention, the combination of a Compound of the Invention and one or more second therapeutic agents as described in Methods I-A, II-A or any of 9.1-9.38, may be administered as a Pharmaceutical Composition or a depot Composition as hereinbefore described. Similarly, the combination of a Compound of the Invention and one or more second therapeutic agents as described in Methods I_(p)-A, II_(p)-A or any of 9.1-9.38, may be administered as a Pharmaceutical Composition or a depot Composition as hereinbefore described. The combination compositions can include mixtures of the combined drugs, as well as two or more separate compositions of the drugs, which individual compositions can be, for example, co-administered together to a patient.

In a particular embodiment, Methods I-A, II-A, I_(p)-A, II_(p)-A or any of 9.1-9.38 comprises administering to a patient in need thereof, a Compound of the Invention in combination with an atypical antipsychotic agent, e.g., a compound selected from clozapine, aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, in free or pharmaceutically acceptable salt form, for example wherein the dosage of the atypical antipsychotic agent is reduced and/or side effects are reduced.

In another embodiment, Methods I-A, II-A, Methods I_(p)-A, II_(p)-A or any of 9.1-9.38 comprises administering to a patient in need thereof, a Compound of the Invention in combination with an anti-depressant, e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, or velafaxine, in free or pharmaceutically acceptable salt form. Alternatively, the anti-depressant may be used as an adjunct medication in addition to the compounds of the Invention.

In still another embodiment, Methods I-A, II-A, I_(p)-A, II_(p)-A or any of 9.1-9.38 comprises administering to a patient in need thereof, a Compound of the Invention in combination with a compound that modulates GABA activity, e.g., a compound selected from doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam or any combinations thereof, in free or pharmaceutically acceptable salt form.

In another particular embodiment, Methods I-A, II-A, I_(p)-A, II_(p)-A or any of 9.1-9.38 comprises administering to a patient in need thereof, a Compound of the Invention in combination with doxepin in free or pharmaceutically acceptable salt form. Dosages of doxepin can vary in any range known to a person of ordinary skill in the art. In one example, a 10 mg dose of doxepin may be combined with any dosage of a compound of the Invention.

In another embodiment, Methods I-A, II-A, I_(p)-A, II_(p)-A or any of 9.1-9.38 comprises administering to a patient in need thereof, a Compound of the Invention in combination (including as part of a daily dosage regimen) with an atypical stimulant, e.g., a modafinil, adrafinil, or armodafinil. A regimin incorporating a Compound of the Invention with such drugs promotes more regular sleep, and avoids side effects such as psychosis or mania associated with higher levels of such drugs, e.g., in the treatment of bipolar depression, cognition associated with schizophrenia, and excessive sleepiness and fatigue in conditions such as Parkinson's disease and cancer.

In the eighth aspect, the invention provides use of a compound as described in the following formulae:

-   -   11.1 Compound of Formula I or any of formulae 1.1-1.14, in free         or pharmaceutically acceptable salt form;     -   11.2 a Pharmaceutical Composition as hereinbefore described;     -   11.3 Depot Composition as hereinbefore described; or     -   11.4 Osmotic-controlled Release Oral delivery System Composition         as hereinbefore described,         (in the manufacture of a medicament) for the treatment or         prophylaxis of one or more disorders as disclosed hereinbefore,         e.g., in any of Method I, any of 7.1-7.27, Method II, any of         8.1-8.15, Methods I-A, II-A, any of 9.1-9.38, Method I_(P),         Method II_(P), Methods I_(P)-A, II_(P)-A, or any methods         described in the sixth or seventh aspect of the invention.

In the ninth aspect, the invention provides a pharmaceutical composition as hereinbefore described, e.g., in the following formulae:

-   -   12.1 a Pharmaceutical Composition as hereinbefore described;     -   12.2 Depot Composition as hereinbefore described; or     -   12.3 Osmotic-controlled Release Oral delivery System Composition         as hereinbefore described,         for use in the treatment or prophylaxis of one or more disorders         as disclosed hereinbefore, e.g., in any of Method I, any of         7.1-7.27, Method II, any of 8.1-8.15, Methods I-A, II-A, any of         9.1-9.38, Method I_(P), Method II_(P), Methods I_(P)-A,         II_(P)-A, or any methods described in the sixth or seventh         aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms as used herein have the following meetings:

-   -   a. “Alkyl” as used herein is a saturated or unsaturated         hydrocarbon moiety, e.g., one to six carbon atom, e.g., one to         four carbon atom in length, which may be linear or branched         (e.g., n-butyl or tert-butyl), unless otherwise specified.

Unless otherwise indicated, the Compounds of the Invention, e.g., Compounds of Formula I or any of 1.1-1.14, or any of formulae 4.1-4.4 may exist in free or salt, e.g., as acid addition salts, form. An acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, acid acetic, trifluoroacetic, citric, maleic acid, toluene sulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like. In addition a salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)-amine. In a particular embodiment, the salt of the Compounds of the Invention is a toluenesulfonic acid addition salt. In another particular embodiment, the salt of the Compounds of the Invention is a fumeric acid addition salt. In a particular embodiment, the salt of the Compounds of the Invention is a phosphoric acid addition salt.

The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention, and are therefore also included.

The Compounds of the Invention may comprise one or more chiral carbon atoms. The compounds thus exist in individual isomeric, e.g., enantiomeric or diasteriomeric form or as mixtures of individual forms, e.g., racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration. The invention is to be understood as embracing both individual optically active isomers as well as mixtures (e.g., racemic/diasteromeric mixtures) thereof. Accordingly, the Compounds of the Invention may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess (“ee”), preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (Z) or trans (E) form, and both isomeric forms are encompassed within the scope of this invention.

Compounds of the Invention may in some cases also exist in prodrug form. The term “prodrug” is an art recognized term and refers to a drug precursor prior to administration, but generates or releases the active metabolite in vivo following administration, via some chemical or physiological process. In some instances, the Compounds of the Invention may be a prodrug as well as a metabolite. Our inventors have found that by blocking the in vivo back formation of the active 1-(4-Fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, the Compounds of the Invention would prevent dopamine antagonism while maintaining binding to 5-HT_(2A) and SERT.

Wherein X is —N(CH₃)—, the Compounds of the Invention may further be metabolized in vivo to form the des-methyl derivative (i.e., wherein X is —N(H)—. In particular, the Compound of Formula I, wherein X is —N(CH₃) and Y is —C(H)(OH)— or —C(═O), may be metabolized to form the des-methyl derivative (e.g., wherein X is —N(H)— and Y is —C(H)(OH) or —C(═O)— respectively), wherein the hydroxy compound may then be oxidized in vivo to form the respective active desmethyl Compound of Formula Q, wherein X—N(H)— and Y is —C(═O).

Similarly, wherein the Compounds of the Invention contain an amine group, prodrug of such amine, e.g., methyl amine prodrugs may also exist wherein the prodrug is cleaved to release the amine metabolite in vivo following administration.

Alternatively and/or additionally, the Compounds of the Invention may be included as a depot formulation, e.g., by dispersing, dissolving or encapsulating the Compounds of the Invention in a polymeric matrix as described in the second and third aspect, such that the Compound is continually released as the polymer degrades over time. The release of the Compounds of the Invention from the polymeric matrix provides for the controlled- and/or delayed- and/or sustained-release of the Compounds, e.g., from the pharmaceutical depot composition, into a subject, for example a warm-blooded animal such as man, to which the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the Compounds of the Invention to the subject at concentrations effective for treatment of the particular disease or medical condition over a sustained period of time, e.g., 14-180 days, preferably about 30, about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of the Invention (e.g., Depot composition of the Invention) may include a polyester of a hydroxyfatty acid and derivatives thereof or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethyleneglycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethylene oxalate or polytetramethylene oxalate), a polyortho ester, a polycarbonate (for example polyethylene carbonate or polyethylenepropylene carbonate), a polyortho-carbonate, a polyamino acid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and the like, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/or graft copolymers. When the above alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-isomers, L-isomers and/or DL-isomers may be used. Among others, alpha-hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), its ester, poly-alpha-cyanoacrylic acid esters, etc. may be used, and lactic acid-glycolic acid copolymer (also referred to as poly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), and hereinafter referred to as PLGA) are preferred. Thus, in one aspect the polymer useful for the polymeric matrix is PLGA. As used herein, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is the biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is a biocompatible and biodegradable polymeric material. The term “biocompatible” is defined as a polymeric material that is not toxic, is not carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable wherein the polymeric material should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body in that the polymeric matrix is biocompatible with the body. Particular useful examples of polymeric matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. The preferred polymer for use in the practice of this invention is dl(polylactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of from about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Dependent on the rate of degradation to be achieved, different molecular weight of polymers may be used. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymeric matrix and then degrade. The drug can also be released from the polymeric matrix as the polymeric excipient bioerodes.

The PLGA may be prepared by any conventional method, or may be commercially available. For example, PLGA can be produced by ring-opening polymerisation with a suitable catalyst from cyclic lactide, glycolide, etc. (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

It is believed that PLGA is biodegradable by means of the degradation of the entire solid polymer composition, due to the break-down of hydrolysable and enzymatically cleavable ester linkages under biological conditions (for example in the presence of water and biological enzymes found in tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which may further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade by means of hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal such as man, to produce lactic acid and glycolic acid and create the acidic microclimate. Lactic and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as man under normal physiological conditions and therefore are well tolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention may comprise a star polymer wherein the structure of the polyester is star-shaped. These polyesters have a single polyol residue as a central moiety surrounded by acid residue chains. The polyol moiety may be, e. g., glucose or, e. g., mannitol. These esters are known and described in GB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which are incorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g., polyol, e. g., glucose or mannitol as the initiator. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to about 20,000 Daltons, with at least 1, preferably at least 2, e. g., as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain polylactide or co-polylactide chains. The branched polyesters, e. g., poly(d,l-lactide-co-glycolide) have a central glucose moiety having rays of linear polylactide chains.

The depot composition of the invention as hereinbefore described may comprise the polymer in the form of microparticles or nanoparticles, or in a liquid form, with the Compounds of the Invention dispersed or encapsulated therein. “Microparticles” is meant solid particles that contain the Compounds of the Invention either in solution or in solid form wherein such compound is dispersed or dissolved within the polymer that serves as the matrix of the particle. By an appropriate selection of polymeric materials, a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.

When the polymer is in the form of microparticles, the microparticles may be prepared using any appropriate method, such as by a solvent evaporation or solvent extraction method. For example, in the solvent evaporation method, the Compounds of the Invention and the polymer may be dissolved in a volatile organic solvent (for example a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile, or an alcohol such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabiliser (for example polyvinyl alcohol, PVA). The organic solvent is then evaporated to provide microparticles with the Compounds of the Invention encapsulated therein. In the solvent extraction method, the Compounds of the Invention and polymer may be dissolved in a polar solvent (such as acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (such as a water/PVA solution). An emulsion is produced to provide microparticles with the Compounds of the Invention encapsulated therein. Spray drying is an alternative manufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is also described in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840.

The microparticle of the present invention can be prepared by any method capable of producing microparticles in a size range acceptable for use in an injectable composition. One preferred method of preparation is that described in U.S. Pat. No. 4,389,330. In this method the active agent is dissolved or dispersed in an appropriate solvent. To the agent-containing medium is added the polymeric matrix material in an amount relative to the active ingredient that provides a product having the desired loading of active agent. Optionally, all of the ingredients of the microparticle product can be blended in the solvent medium together.

Solvents for the Compounds of the Invention and the polymeric matrix material that can be employed in the practice of the present invention include organic solvents, such as acetone; halogenated hydrocarbons, such as chloroform, methylene chloride, and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and the like. In one embodiment, the solvent for use in the practice of the present invention may be a mixture of benzyl alcohol and ethyl acetate. Further information for the preparation of microparticles useful for the invention can be found in U.S. Patent Publication Number 2008/0069885, the contents of which are incorporated herein by reference in their entirety.

The amount of the Compounds of the Invention incorporated in the microparticles usually ranges from about 1 wt % to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight % is meant parts of the Compounds of the Invention per total weight of microparticle.

The pharmaceutical depot may comprise a pharmaceutically-acceptable diluent or carrier, such as a water miscible diluent or carrier.

Details of Osmotic-controlled Release Oral delivery System composition may be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO 2000/35419, the contents of each of which are incorporated by reference in their entirety.

A “therapeutically effective amount” is any amount of the Compounds of the invention (for example as contained in the pharmaceutical depot) which, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or regression of the disease or disorder over the period of time as intended for the treatment.

Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular Compounds of the Invention used, the mode of administration, and the therapy desired. Unless otherwise indicated, an amount of the Compounds of the Invention for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the Compound of the Invention in free base form (i.e., the calculation of the amount is based on the free base amount).

Compounds of the Invention may be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscular or subcutaneous) or transdermally, but are preferably administered orally. In certain embodiment, the Compounds of the Invention, e.g., in depot formulation, is preferably administered parenterally, e.g., by injection.

In general, satisfactory results for Method I or any of formulae 7.1-7.27 or Method I_(P) or use of the Compounds of the Invention as hereinbefore described, e.g. for the treatment of a combination of diseases such as a combination of at least depression, psychosis, e.g., (1) psychosis, e.g., schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from psychosis, e.g., schizophrenia; (3) mood disorders associated with psychosis, e.g., schizophrenia, or Parkinson's disease; and (4) sleep disorders associated with psychosis, e.g., schizophrenia, or Parkinson's disease, as set forth above are indicated to be obtained on oral administration at dosages of the order from about 1 mg to 100 mg once daily, preferably about 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferably via oral administration.

Satisfactory results for Method II or any of 8.1-8.15, Method II_(P) or use of the Compounds of the Invention as hereinbefore described, e.g. for the treatment of sleep disorder alone or agitation, aggressive behaviors, post-traumatic stress disorder or impulse control disorder alone, e.g., intermittent explosive disorder alone are indicated to be obtained on oral administration at dosages of the order from about 1 mg-10 mg once daily, e.g., about 2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg, 5 mg or 10 mg, of a Compound of the Invention, in free or pharmaceutically acceptable salt form, once daily, preferably via oral administration.

Satisfactory results for Method I-A or any of 9.1-9.38 or Method I_(P)-A are indicated to be obtained at less than 100 mg, preferably less than 50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactory results for Method II-A or any of 9.1-9.38 are indicated to be obtained at less than 10 mg, e.g., less than 5 mg or, preferably less than 2.5 mg.

For treatment of the disorders disclosed herein wherein the depot composition is used to achieve longer duration of action, the dosages will be higher relative to the shorter action composition, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greater than 1000 mg. Duration of action of the Compounds of the Invention may be controlled by manipulation of the polymer composition, i.e., the polymer:drug ratio and microparticle size. Wherein the composition of the invention is a depot composition, administration by injection is preferred.

The pharmaceutically acceptable salts of the Compounds of the Invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further details for the preparation of these salts, e.g., toluenesulfonic salt in amorphous or crystal form, may be found in PCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients (an example include, but is not limited to sesame oil) and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

Methods of Making the Compounds of the Invention:

The intermediates of the Compounds of the Invention may be prepared as described in WO PCT/US08/03340 (WO 2008/112280); U.S. application Ser. No. 10/786,935; U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, the contents of which are incorporated by reference in their entirety. Salts of the Compounds of the Invention may also be prepared as similarly described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680; U.S. RE39679; and WO 2009/114181, the contents of each of which are incorporated by reference in their entirety.

Isolation or purification of the diastereomers of the Compounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving beds and the like.

The Compound of Formula I, wherein R² is —OR³ wherein R³ is H, may be prepared by reacting Int-A with a Grignard reagent, R¹—MgX² wherein X² is halide, e.g., bromide or chloride, preferably bromide, R¹ and X are defined in Formula I, e.g., R¹ is methyl and X is for example N(CH₃), e.g., in a solvent such as tetrahydrofuran or diethyl ether, preferably tetrahydrofuran. The reaction may be summarized in the reaction scheme below:

The Compound of Formula I, wherein R² is —OR³ wherein R³ is C₁₋₆alkyl may be prepared by reacting Int-B with R³—OH and BF3.OEt wherein R³ is C₁₋₆alkyl. The reaction may be summarized in the reaction scheme below:

Example 1 2-(4-Fluoro-phenyl)-5-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-pentan-2-ol

To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (99 mg, 0.25 mmol) in THF is added 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) dropwise at 0° C. Upon the completion of the addition of CH₃MgBr, the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. Another batch of 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) is added dropwise, and the reaction mixture was stirred at room temperature overnight. The mixture is carefully quenched with water, basified with saturated sodium bicarbonate, and then extracted with methylene chloride four times. The combined organic phase is evaporated to dryness, and the residue is purified on a basic alumina column to give 28 mg of pure product as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 8.22 (br, 1H), 7.58-7.37 (m, 2H), 7.07 (t, J=8.5 Hz, 1H), 7.01 (t, J=8.7 Hz, 1H), 6.65 (dt, J=10.6, 7.7 Hz, 1H), 6.57-6.29 (m, 2H), 3.59 (td, J=11.1, 3.0 Hz, 1H), 3.37-3.12 (m, 4H), 3.00-2.65 (m, 5H), 2.55-2.13 (m, 5H), 2.12-1.78 (m, 4H), 1.69-1.30 (m, 5H). MS (ESI) m/z 410.2 [M+H]⁺.

Example 2 (6bR,10aS)-8-[4-(4-Fluoro-phenyl)-4-methoxy-butyl]-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-ol (225 mg, 0.57 mmol) in anhydrous dichloromethane (3 mL) is added anhydrous methanol (100 μL, 2.28 mmol), and then BF₃.OEt (300 μL, 2.28 mmol, 1.0 M in THF) is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight, and then poured into ice water. After the mixture is basified with triethylamine, the organic phase is separated and dried over MgSO₄, and then evaporated to dryness under reduced pressure. The obtained residue is purified with a semi-preparative HPLC system to give 80 mg of pure product as a brown oil. ¹H NMR (500 MHz, DMSO-d₆) δ 7.31 (ddd, J=8.6, 5.6, 1.2 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 6.50 (td, J=7.6, 1.3 Hz, 1H), 6.39 (d, J=7.3 Hz, 1H), 6.32 (d, J=7.9 Hz, 1H), 4.15 (td, J=6.5, 3.5 Hz, 1H), 3.49-3.37 (m, 1H), 3.31-3.22 (m, 3H), 3.15-3.04 (m, 4H), 3.02-2.91 (m, 1H), 2.77 (s, 3H), 2.70-2.61 (m, 2H), 2.29-2.11 (m, 2H), 2.09-1.97 (m, 1H), 1.92-1.81 (m, 1H), 1.78-1.63 (m, 3H), 1.60-1.49 (m, 1H), 1.49-1.37 (m, 1H), 1.37-1.22 (m, 1H). MS (ESI) m/z 410.6 [M+H]⁺.

Example 3 Receptor Binding Activity

Binding to 5HT_(2A), D₂ and SERT is assessed, using the methods described in WO/2009/145900. The compounds of Examples 1 and 2 are found to have potent binding to 5-HT_(2A), SERT and D₂, with affinity constants in the sub-micromolar range:

Receptor Ki (nM) for Ex. 1 Ki (nM) for Ex. 2 5-HT_(2A) 350 96 D₂ 740 810 SERT 520 300 

1. A compound of formula I:

wherein: X is N(H), N(C₁₋₄alkyl) or O; R¹ is H or C₁₋₆alkyl (e.g., methyl); R² is H or OR³ wherein R³ is H or C₁₋₆alkyl (e.g., methyl); provided that R¹ and R² are not both H, and R¹ and R³ are not both H; in free or salt form.
 2. The compound according to claim 1, wherein R² is OR³.
 3. The compound according to claim 2, wherein R¹ is C₁₋₆alkyl.
 4. The compound according to claim 3, wherein R¹ is methyl.
 5. The compound according to claim 1, wherein R² is OR³ and R³ is C₁₋₆alkyl.
 6. The compound according to claim 5 wherein R² is OR³ and R³ is methyl.
 7. The compound according to claim 1, wherein X is N(C₁₋₄alkyl).
 8. The compound according to claim 1, wherein X is O.
 9. The compound according to claim 1, wherein X is N(H).
 10. The compound according to claim 7, wherein X is N(CH₃).
 11. The compound according to claim 1 which is:


12. The compound according to claim 1 which is:


13. The compound according to claim 1, wherein said compound is in salt form.
 14. The compound according to claim 13, wherein the salt is selected from a group consisting of toluenesulfonic, fumeric and phosphoric acid addition salt.
 15. A pharmaceutical composition comprising the compound according to claim 1, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier.
 16. A method for the treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof an active amount of the compound according to claim 1, in free or pharmaceutically acceptable salt form.
 17. The method according to claim 16, wherein said disorder is selected from a group consisting of obesity, anxiety, depression, refractory depression, psychosis, schizophrenia, sleep disorders, sleep disorders associated with schizophrenia and other psychiatric and neurological diseases, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, agitation, agitation in dementia, agitation in Alzheimer's disease, agitation in autism and related autistic disorders, gastrointestinal disorders, dysfunction of the gastrointestinal tract motility, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.
 18. The method according to claim 16, wherein said disorder is one or more disorders associated with dementia, mild cognition impairment and dementing illnesses, senile dementia, Alzheimer's disease, Pick's disease, frontotemporal dementia, parasupranculear palsy, dementia with Lewy bodies, vascular dementia, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoff's syndrome, corticobasal degenerations and prion disease.
 19. The method according to claim 16, wherein said disorder is a disorder involving serotonine 5-HT_(2A), dopamine D2 and/or serotonin reuptake transporter (SERT) pathway.
 20. The method according to claim 16, wherein said disorder is one or more disorders selected from the group consisting of schizophrenia, depression, anxiety, sleep disorder, agitation, aggressive behaviors, post-traumatic stress disorder and impulse control disorder.
 21. The method according to claim 20, wherein said disorder is schizophrenia.
 22. The method according to claim 20, wherein said disorder is post-traumatic stress disorder.
 23. The method according to claim 20, wherein said disorder is impulse control disorder.
 24. The method according to claim 23, wherein said disorder is intermittent explosive disorder.
 25. The method according to claim 16, wherein said disorder is agitation or aggressive behaviors.
 26. A pharmaceutical composition comprising the compound according to claim 1, in free or pharmaceutically acceptable salt form, in a polymeric matrix.
 27. The pharmaceutical composition according to claim 26, wherein the polymeric matrix comprises poly(d,l-lactide-co-glycolide).
 28. The pharmaceutical composition according to claim 27, wherein the molar ratio of lactide to glycolide in such a copolymer is about 75:25.
 29. The pharmaceutical composition according to claim 26, wherein the compound is in the form of microparticles or nanoparticles. 